First Report of a Known Pathogenic Variant in the FZD6 Gene, in an Iranian Family with Recessive Nail Dysplasia: A Case Report.

Congenital Nail abnormalities are rare ectodermal defects. Autosomal recessive nail dysplasia is much rarer. Recently it has been recognized as a condition resulting in nail dystrophy in the absence of other cutaneous or extracutaneous disorders. Few case reports have identified mutations in the Frizzled 6 (FZD6) gene in families presenting with abnormal nails consistent with Non-Syndromic Congenital Nail Dysplasia. We report a family presenting, they lived in Namin a country of the Ardabil Province, northwestern Iran in 2016, for the first time in Iran in whom we identified mutations in FZD6 with abnormal nails formation.


Introduction
Congenital Nail abnormalities are rare ectodermal defects. Including very rare conditions nail dysplasia. These defects may show no significant changes or complete absence of nails (1,2). Wnt-FZD signaling pathway plays an important role in the development of ectodermal appendages including nails. Mutations in the gene Frizzled 6 (FZD6) can cause autosomal-recessive nail dysplasia (2)(3)(4). We have recently identified clinical presentation of the nail disorder with a mutation in the gene frizzled causing isolated nail dysplasia in a Turkish family from Namin a country of the Ardabil Province, northwestern Iran. Some people in this area have nail dysplasia where all fingernails and toenails were claw-shaped and thickened from childhood. This report describes a previously known missense mutation in the mentioned gene in an Iranian family, a condition reported for the first time in Iran.

Case Report
A 26-yr-old male medical student of Ardabil University of Medical Sciences in 2016, born of a healthy non-consanguineous parent's but the same region, referred to the genetic clinic with nail dysplasia. On clinical examination, all of the 20-nail was a variable degree of nail dystrophy, hyperkeratosis onychauxis (thick nails), hyponychia, onycholysis and claw-appearance with yellow bed (Fig.1). From the age of about 1 year; his nails became thickened, claw-shaped and hyperplastic but did not seem to grow out. The growing of toenails was very slower than fingernails. At first, his thumb of hands was thicker, hyperplastic and discolored and then all of the nails had symmetrical involvement the same sign. Having dealt with the surrounding surfaces deformed nail was cracked at the cuticle and extremely painful and bleeding, then separated from the nail bed and fall. The hyperkeratotic nails developed into claw-like structures on completion of the first decade of life possibly because of an outgrowth from below the edge of the nail. No associated abnormality was found in the affected individual in his hair, teeth, skin, and scalp. Since four years ago, he has had numerous medical problems. Such as GERD, lymphedematous on the left leg, rhinitis allergic, Lung CT Scan showed that he had allergic asthma, and abdominal ultrasonography revealed fatty liver changes in grade 4. His sister and brother were 21 and 20 yr old. His sister is healthy but his brother has the same signs and symptoms in his toenails and fingernails (Fig.2). All observed nail abnormalities were a similar pattern of ticking and detachment of the nail from the nail bed of fingernails and toenails in both boys of this family. He had 16 aunt and uncles with no problem in their nails. He is married and his non-consanguineous wife from another country of the Ardabil Province. She was healthy and they had no child.      Fig. 3. Circles and squares represent females and males, respectively. Clear symbols represent unaffected and filled symbols represent affected individuals. After the gene analyzed, the proband was homozygous for FZD6 mutation c.1531C>T (p. Arg511Cys) (Fig.4). In addition, siblings and par-ents were also sequenced, to confirm appropriate co-segregation of the allele within the family. His younger affected brother was homozygous for the FZD6 mutation (Fig. 5). His unaffected parents and sister were all heterozygous for the mutation (Fig. 6).
Sequence analysis of FZD6, as the most promising gene, identified a homozygous missense mutation, in exon 4 of the gene FZD6 in both affected individuals of our family. This missense mutation is concordant with S.I. Raza report, identified for the first time, all with Pakistani origin (2, 7). The missense mutation involves a C to T transition at nucleotide position 1531(c.1531C>T) substituting Arginine with Cysteine at amino acid position 511 (p. Arg511Cys). The two patients were homozygous for variant p. Arg511Cys, their parents and their normal sister were heterozygous, thus the variant co-segregated with the disease phenotype. This is an already known mutation reported for the fourth time in the world and the first time in Iran. The C>T transition changes the codon CGC (encoding arginine) to TGC (encoding cysteine) "rs number 151339003". S.I. Raza reported the same mutation has been previously in another Pakistani family (5, 7). All proband had a variable degree of nail dysplasia and them homozygous for carrying mutation FDZ6 (1,2,(8)(9)(10). During normal nail formation, the nail plate must be properly attached to the nail bed. Keratins constitute a major component of the cytoskeleton of the differentiated nail plate, and expression of FZD6 in the nail plate corresponded to the figure and shape of affected individuals (3,11). The missense mutation (p. Arg511Cys) was identified in the present study, lies in the sixth transmembrane domain of the mutant FZD6. Considering the effect of the missense mutation (p. Arg511Cys) described the mutation (p. Arg511Cys) lies in the transmembrane domain, it is possible that mutant FZD6 reaches to the plasma membrane and can affect the binding of Wnt ligand with FZD6, which in turn will affect recruitment of intracellular protein.
Dermatologists should consider the genetic analysis of individuals with hereditary isolated nail dysplasia, which aids in correct genetic counseling for their family.

Ethical considerations
Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.